In recent years, patients with diseases associated with muscle tissue degeneration, such as cardiomyopathy, muscular dystrophy, pulmonary fibrosis and the like, have been increasing in number, and greater attention has been paid to the prophylaxis and treatment of these diseases.
Cardiomyopathy is an idiopathic disease of cardiac muscle and is classified into dilated (congestive) cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy and the like. The dilated cardiomyopathy is characterized by ventricular dilation and lower contraction function, wherein degeneration and atrophy of cardiac muscle of left ventricle or both ventricles and fibrosis of interstitium are observed. It shows the state of congestive heart failure, and is associated with grave convalescence. Hypertrophic cardiomyopathy accompanies nonuniform thickening of ventricle and irregular alignment of cardiac muscle cells (intricate alignment) mainly in the interventricular septum, and the convalescence varies from no symptom to heart failure, sudden death and the like. Restrictive cardiomyopathy mostly accompanies dilation disorder caused by endocardial or subendocardial fibrous hyperplasia, and is extremely intractable.
The treatment of cardiomyopathy includes administration of vasodilators (e.g., prazosin, hydralazine and the like), angiotensin conversion enzyme inhibitors (e.g., captopril and the like) and the like for symptomatic therapy of dilated cardiomyopathy. As a complete cure, heart transplantation is effective, but the operation is unfeasible in our country. To treat hypertrophic cardiomyopathy, .beta. blockers (e.g., propranolol and the like) and Ca antagonists (e.g., verapamil, diltiazem and the like) have been used.
The above-mentioned treatments currently applied in our country, nevertheless, are all symptomatic therapies of various symptoms of cardiomyopathy, and are not complete cures that improve degeneration itself of the cardiac muscle. In other words, conventional treatment methods cannot positively suppress the progression of the disease conditions, and therefore, the criticality of heart failure, sudden death and the like associated with patients with cardiomyopathy cannot be reduced with ease.
In addition, there exists no effective medication of muscular dystrophy or pulmonary fibrosis.
On the other hand, angiotensin II antagonist, which is effective for the treatment of hypertension and the like, has been attracting much attention in recent years. The angiotensin II antagonist is a medication that prevents, at a receptor on the cell membrane, angiotensin II, that shows strong vasocontraction and acts on adrenal cortex to promote secretion of aldosterone, thereby causing higher blood pressure, from functioning via the receptor.
Nakamura et al. reported (Am. J. Physiol. Dec. 1994, 267, H2297-2304) that a representative angiotensin II antagonist, TCV-116, was investigated for the action on hamsters with cardiomyopathy, but the action of this drug, which was administered in a high dose, was only the improvement of heart function and that the drug failed to show a basic histological improvement.
Under the circumstances, there is a demand for the development of a medication that can inhibit or improve degeneration of muscle tissues, such as necrosis, fibrosis, calcification and the like, and that is capable of preventing or completely treating cardiomyopathy, muscular dystrophy, pulmonary fibrosis and the like by this action.
It is therefore an object of the present invention to provide a prophylactic and therapeutic agent of muscle tissue degeneration, which is capable of inhibiting or improving necrosis, fibrosis, calcification and the like of muscle tissues.